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| Status |
Public on May 28, 2018 |
| Title |
The whole genome effects of the PPARα agonist fenofibrate on livers of hepatocyte humanized mice |
| Platform organism |
Homo sapiens |
| Sample organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
The role of PPARα in gene regulation in mouse liver is well characterized. However, less is known about the effect of PPARα activation in human liver. The aim of the present study was to better characterize the impact of PPARα activation on gene regulation in human liver by combining transcriptomics with the use of hepatocyte humanized livers. To that end, chimeric mice containing hepatocyte humanized livers were given an oral dose of 300 mg/kg fenofibrate daily for 4 days. Livers were collected and analysed by hematoxilin and eosin staining, qPCR, and transcriptomics. Transcriptomics data were compared with existing datasets on fenofibrate treatment in normal mice. The human hepatocytes exhibited excessive lipid accumulation. Fenofibrate increased the size of the mouse but not human hepatocytes, and tended to reduce steatosis in the human hepatocytes. Quantitative PCR indicated that induction of PPARα targets by fenofibrate was less pronounced in the human hepatocytes than in the residual mouse hepatocytes. Transcriptomics analysis indicated that, after filtering, a total of 282 genes was significantly different between fenofibrate- and control-treated mice (P<0.01). 123 genes were significantly lower and 159 genes significantly higher in the fenofibrate-treated mice, including many established PPARα targets such as FABP1, HADHB, HADHA, VNN1, PLIN2, ACADVL and HMGCS2. According to gene set enrichment analysis, fenofibrate upregulated interferon/cytokine signaling-related pathways in hepatocyte humanized liver, but downregulated these pathways in normal mouse liver. Also, fenofibrate downregulated pathways related to DNA synthesis in hepatocyte humanized liver but not in normal mouse liver. The results support the major role of PPARα in regulating hepatic lipid metabolism, and underscore the more modest effect of PPARα activation on gene regulation in human liver compared to mouse liver. The data suggest that PPARα may have a suppressive effect on DNA synthesis in human liver, and a stimulatory effect on interferon/cytokine signalling.
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| Overall design |
Chimeric mice with humanized livers were given an oral dose of 300 mg/kg fenofibrate daily for 4 days after which the hepatic transcriptome was analyzed.
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| Contributor(s) |
de la Rosa Rodriguez MA, Sugahara G, Ishida Y, Tateno C, Kersten S |
| Citation(s) |
29879903 |
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| Submission date |
Nov 16, 2017 |
| Last update date |
Aug 27, 2018 |
| Contact name |
Guido Hooiveld |
| E-mail(s) |
guido.hooiveld@wur.nl
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| Organization name |
Wageningen University
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| Department |
Div. Human Nutrition & Health
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| Lab |
Nutrition, Metabolism & Genomics Group
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| Street address |
HELIX, Stippeneng 4
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| City |
Wageningen |
| ZIP/Postal code |
NL-6708WE |
| Country |
Netherlands |
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| Platforms (1) |
| GPL11532 |
[HuGene-1_1-st] Affymetrix Human Gene 1.1 ST Array [transcript (gene) version] |
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| Samples (6)
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| GSM2859983 |
Humanized mouse liver, control treatment, replicate 1 |
| GSM2859984 |
Humanized mouse liver, control treatment, replicate 2 |
| GSM2859985 |
Humanized mouse liver, control treatment, replicate 3 |
| GSM2859986 |
Humanized mouse liver, fenofibrate treatment, replicate 1 |
| GSM2859987 |
Humanized mouse liver, fenofibrate treatment, replicate 2 |
| GSM2859988 |
Humanized mouse liver, fenofibrate treatment, replicate 3 |
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| Relations |
| BioProject |
PRJNA418862 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE107041_RAW.tar |
23.8 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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